title: Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.
abstract: If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rood
authors.forename: Amy M
authors.initials: AM
authors.lastname: Berkley
authors.forename: Tiffany
authors.initials: T
authors.lastname: Guo
authors.forename: Daniel
authors.initials: D
authors.lastname: Mendoza
authors.forename: Andy
authors.initials: A
authors.lastname: Patamawenu
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Cogliano
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Ann
authors.initials: A
authors.lastname: Duerr
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
mesh_terms: D016915:AIDS Vaccines / Q000627:therapeutic use*; D000256:Adenoviridae / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D020276:HIV Long-Term Survivors; D006679:HIV Seropositivity / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D013602:T-Lymphocytes, Cytotoxic; D014779:Virus Replication
chemical_list: D016915:AIDS Vaccines; D015235:HLA-B Antigens